Neurotransmitter serotonin or 5-Hydroxytryptamine (5-HT) is abundantly distributed in the central nervous system, including hippocampus and frontal cortex. 5-HT receptors are a family of G-protein coupled receptors, characterized with 7-transmembrane helices and presently have fourteen known receptor subtypes, some of which exist as multiple splice variants [D. L. Murphy, A. M. Andrews, C. H. Wichems, Q. Li, M. Tohda and B. Greenberg, J. Clin. Psychiatry, 1998, 59 (suppl. 15), 4]. 5-HT influences a number of physiological functions and is implicated in a large number of central nervous system disorders and neurodegenerative diseases [W. E. Childers, Jr. and A. J. Robichaud, Ann. Rep. Med. Chem. 2005, 40, 17].
The 5-HT4 receptors are a member of the superfamily of G-protein coupled receptors with seven transmembrane (7TM) domains coupled to a G-protein which is positively coupled to adenylate cyclase. The 5-HT4 receptors are expressed in a wide variety of tissues, including the human brain and the rodent brain, and human, dog, pig and rodent gastro-intestinal tract, and the pig and human heart. In the human brain, the presence of 5-HT4 receptors has been shown in basal ganglia and in the caudate putamen nuclei, where the density is the highest [Bonacenture, Hall, Gommersen, Cras, langlois, Jurzak, Leysen, Synapse, 2000, 36, 35]. In the mammalian brain, the 5-HT4 receptors contribute to dopamine secretion and regulate learning and long-term memory via the modification of acetylcholine release. In the central nervous system of guinea-pigs and rats, 5-HT4 receptors are expressed in two anatomical and functional structures: the extrapyramidal motor system and the mesolimbic system [Patel, Roberts, Moorman, Reavill, Neuroscience, 1995, 69, 1159; Grossman, Kilpatrik, Bunce, Br. J. Pharmacol. 1993, 109, 618].
In the peripheral tissues, the 5-HT4 receptors have proven to regulate gastro-intestinal tract motility, intestinal electrolyte secretion, adrenal secretion of corticosteroids, bladder contraction and atrium contractility. Significant advances have been made in the 5-HT4 receptor studies during the past decade that culminated in the development of 5-HT4 agonists and partial agonists, e.g. Tegaserod, for the treatment of irritable bowel syndrome [Giger, Mattes, Pfannkuche, Ann. Rep Med. Chem. 2007, 42, 195].
The 5-HT4 receptors are involved in a wide variety of central and peripheral disorders, including neurodegenerative disorders such as Alzheimer's disease, cognition disorders, cognitive impairment, memory dysfunction, irritable bowel syndrome, nausea, emesis, vomiting, prokinesia, gastroesophageal reflux disease, nonulcer dyspepsia, depression, anxiety, urinary incontinence, migraine, arrhthymia, atrial fibrillation, ischemic stroke, gastritis, gastric emptying disorders, feeding disorders, gastrointestinal disorders, constipation, erectile dysfunction, and respiratory depression.
The role of the 5-HT4 receptor has been implicated in the pathology of Alzheimer's disease and related cognitive function [J. Bockaert, S. Claeyseen, V. Compan and A. Dumuis. Curr. Drug. Targets: CNS & Neurolog. Disorders, 2004, 3, 39; P. C. Moser, O. E. Bergis, S. Jegham, A. Lochead, E. Duconseille, T. Elee, J.-P. Terranova, D. Caille, I. Berque-Bestel, F. Lezoualch, R. Fischmeister, A. Dumuis, J. Bockaert, G. Pascal, P. Soubrie and B. Scatton, J. Pharmacol. Exp. Ther. 2002, 302, 731]. A recent report provides evidence from transgenic animal studies that supports the finding that the 5-HT4 receptor is a novel target for cognitive enhancement and that only a partial agonist is needed for producing the beneficial effect in increasing cognition function. Moreover, the 5-HT4 receptor remains functional even in the presence of excess of Aβ peptide and thus offers great potential as a novel target for Alzheimer's drug discovery [J. P. Spencer, J. T. Brown, J. C. Richardson, A. D. Medhurst, S. S. Sehmi, A. R. Calver, A. D. Randall, Neuroscience, 2004, 129, 49]. Stimulation of the 5-HT4 receptor promotes an increase in the production and release of acetylcholine (ACh) in the brain unlike the cholinesterase inhibitors that prevent degradation of ACh for symptomatic improvement in Alzheimer's disease patients.
The activation of 5-HT4 receptor also leads to secretion of the soluble form of amyloid precursor protein (sAPPα), and decrease in Aβ levels via promoting the α-secretase pathway [M. Cachard,-Chastel, F. Lezoualc'h, I. Dewachter, C. Delomenie, S. Croes, H. Devijver, M. Langlois, F. V. Leuven, S. Sicsic, and A. M. Gardier. Brit. J. Pharmacol. 2007, 150, 883]. Evidence in in vivo rat studies of the role of activation of 5-HT4 receptor in the production of sAPPα has recently been reported [S. Cho and Y. Hu, Exper. Neurology, 2007, 203, 274]. The protein, sAPPα is neuroprotective, enhances memory, increases NGF and competes with amyloidogenic (insoluble) APP peptides. Considering the significant evidence reported, it is evident that 5-HT4 receptor agonists may have potential not only in the treatment of Alzheimer's disease but also modification of the disease by slowing and inhibiting its progression [F. Lezoualc'h, Exper. Neurology, 2007, 205, 325].
Activation of the 5-HT4 receptor (5-HT4 receptor partial agonists) has been proposed as one of the more innovative drug targets for cognitive enhancement in neurodegenerative diseases and neuropsychiatric disorders (Wallace T., et al. Pharmacol. Biochem. Behav. 2011, 99, 130-145). The 5-HT4 receptor has also been shown to have potential in the enhancement of learning and memory (King, M. V., et al., Trends Pharmacol. Sci., 2008, 29, 482-492). The 5-HT4 receptor activation has been shown to improve object recognition memory in the rat (Levallet, G., et al. Increased particulate phosphodiesterase 4 in the prefrontal cortex supports 5-HT4 receptor-induced improvement of object recognition memory in the rat, Psychopharmacology, 2009, 202, 125-139). Furthermore, the potential of 5-HT4 partial agonists in the prevention, cure and treatment of cognitive dysfunction in psychiatric disorders have been reviewed in nature reviews of drug discovery published in the February issue of 2012 (Millan, M. J., et al. Cognitive dysfunction in psychiatric disorders: characteristics, causes, and the quest for improved therapy, Nature Reviews, Drug Discovery, 2012, 11, 141-168).
Two new compounds which are potent 5-HT4 receptor partial agonist are currently undergoing clinical trials for drug development for the treatment of Alzheimer's disease and cognitive and memory impairment (Brodney, M. A., et al., J. Med. Chem., 2012, 55, 9240-9254).
Age-related macular degeneration (AMD) is the leading cause of irreversible vision impairment in the aged population. Wet AMD involves abnormal neovascularization under the macula and it is the most damaging form. However, dry AMD, which in advanced forms involves atrophy of the retinal pigment epithelium and photoreceptor cells (known as geographic atrophy), accounts for approximately 90% of all AMD cases. There are no specific drugs on the market for AMD. Prophylactic measures are currently limited to lens implantation and vitamin supplements (based on findings from the Age-related Eye Disease Study, which reduce disease progression in high-risk patients by approximately 25%.
One of the approaches under investigation for the potential prevention and treatment of AMD is to use neuroprotectants such as the 5-HT modulators, more specifically the 5-HT4 receptor partial agonists. A number of possible neuroprotectant products are in clinical development. Tandospirone, a 5-HT1A partial agonist, has completed a Phase 3 clinical trial for the topical treatment of AMD in 2012. Similarly, the investigation of the potential of 5-HT4 partial agonists for the prevention and treatment of AMD is of active interest.
We believe that more promising and potent neuroprotectants such as 5-HT4 partial agonists have a greater potential for the treatment of AMD both by topical application or oral route. The compounds of formula 1 of the present invention have the potential to treat AMD.
5-HT4 receptor agonists have been shown to be effective anti-depressants with a rapid onset of action. It has been shown in several animal (rodents) studies that the administration of a serotonin 5-HT4 receptor agonist induces rapid (3 days) anti-depressants like effects whereas traditional anti-depressants take 2-3 weeks of dosages to produce these effects (Lucas G.; Rymar, V. V.; Du, J.; Mnie-Filali, O.; Haddjeri, N.; Pineyro, G.; Sadikot, A. F.; Debonnel, G., Serotonin (4) (5-HT (4)) receptor agonists are putative antidepressants with a rapid onset of action, Neuron, 2007, 55 (5), 712-725). These findings suggest activation of 5-HT4 receptor as a novel mechanism of anti-depressant action.
The novel compounds of formula 1 have 5-HT4 partial agonist activity and/or full agonist activity, inverse agonist activity and antagonist activity and so have applications as safer and effective therapeutic drugs for the treatment of Alzheimer's disease and age-related cognitive and memory dysfunction and cognitive and memory impairment associated with schizophrenia, depression, ADHD, OCD and other psychiatric disorders and neurodegenerative diseases. These compounds may also have applications in the treatment of gastrointestinal disorders including irritable bowel syndrome, Crohn's disease, gastroesophageal reflux disease, emesis, nausea, vomiting, prokinesia, non-ulcer dyspepcia, anxiety, depression, pain, migraine, urinary incontinence, arterial fibrillation, arrhythmia, ischemic stroke, gastric emptying disorders, gastritis, gastrointestinal disorders, feeding disorders, obesity, anorexia, constipation, constipation, respiratory depression, and erectile dysfunction.